Effect of drug combination on cell viability. As shown by MTT assays (A), a suboptimal concentration of CK2 inhibitor apigenin (10μM) augmented the effect of the PI3-K inhibitor LY294002 on cell viability in cocultures in a synergistic manner. Similarly both compounds synergistically enhanced the effect of fludarabine and could overcome the supportive effect of BMSCs (B). Incubation time was 3 days in coculture, and the data represent the means ± SD of 5 independent experiments. The drug combination index was calculated as reported in Vazquez³⁵  according to the formula: a/A + b/B = I, where (a) is the concentration that inhibits 50% (IC₅₀) of fludarabine in combination with apigenin or LY294002 at concentration (b), A is the IC₅₀ of fludarabine alone; and B is the IC₅₀ apigenin or LY294002 in the absence of fludarabine. (I < 1 means synergistic interaction, I = 1 means additive, and I > 1 means antagonistic interaction.) (C) This model depicts the interaction between CLL cells and the lymphoid microenvironment represented by BMSCs. In this model, CLL cells receive several stimuli from the microenvironment that converge to activate the PI3-K, leading to generation of PIP3, phosphorylation of PDK1 and its downstream target Akt1, resulting in inhibition of apoptosis and prolongation of the lifespan of CLL cells. Because of the phosphorylation of PTEN, which diminishes its ability to convert PIP3 into PIP2, the activation of antiapoptotic PI3-K/Akt cascade persists. This antiapoptotic arm could be effectively counteracted at different sites by the inhibitors of the PI3-K and Akt and the recovery of PTEN activity by the CK2 inhibitors, consequently permitting the induction of spontaneous apoptosis and enhancing the response to cytotoxic compounds in CLL cells.